The present invention comprises a new class of compounds useful in treating diseases, such as diseases, conditions or disorders mediated by integrin receptors, such as vitronectin and fibronectin receptors. In particular, the compounds of the invention and pharmaceutical compositions thereof are useful for the prophylaxis and treatment of diseases, conditions or disorders involving atherosclerosis, restenosis, inflammation, cancer, osteoporosis and the like. This invention also relates to intermediates and processes useful in the preparation of such compounds.
Integrins are heteromeric cell surface receptors many of which have extracellular domains that bind to an Arg-Gly-Asp tripeptide (RDG) found in extracellular (plasma and matrix) proteins, such as fibronectin, vitronectin, fibrinogen and osteopontin. The fibrinogen receptor, gpIIb/IIIa integrin, is a platelet surface receptor that is thought to mediate platelet aggregation and the formation of hemostatic clot at bleeding wound sites (Blood. 71:831, 1988).
Vitronectin receptors, xcex1vxcex23 and xcex1vxcex25 integrin, are expressed by a number of cells, such as endothelial, smooth muscle, osteoclast, bone resorbing, tumor and epithelial cells. Integrin xcex1vxcex23 has been reported to be involved in bone resorption (Endocrinology 137:2347-54, 1996; J. Endocrinol. 154(Suppl.):S47-S56, 1997), in cell attachment, spreading and migration (Int. J. Biochem. Cell Biol. 31:539-544, 1999; Carreitas et al., Int. J. Cancer 80:285-294, 1999), in signal transduction, cell to cell interactions and is upregulated in response to vascular damage (Int. J. Biochem. Cell Biol. 29:721-725, 1997), in tumor cell invasion, angiogenesis, wound healing, phagocytosis of apototic cells and inflammation (J. Cell Biol. 144:767-775, 1999; Drug News Perspect. 10:456-461, 1997; Am. J. Pathol. 148:1407-1421, 1996), in tumor growth and hypercalcemia of malignancy (Cancer Res. 58:1930-1935, 1998), in tumorigenicity of human melanoma cells (Natali et al., Cancer Res. 57:1554-60, 1997), in melanoma metastasis (Cancer Metastasis Rev. 14:241-245, 1995; Cancer Metastasis Rev. 10:3-10, 1991), in the chondrocyte synthesis of matrix metalloproteinases (such as stromelysin, collagenase and gelatinase) which are involved in diseases such as rheumatoid arthritis and osteoarthritis (Arthritis Rheum. 38:1304-1314, 1995), in the progression of the renal injury in Fabry disease (Clin. Chim. Acta 279:55-68, 1999), and in viral infections (J. Virol. 72:3587-3594, 1998; Virology 203:357-65, 1994). Keenan et al. (J. Med. Chem. 40:2289-92, 1997) disclose examples of xcex1vxcex23 inhibitors which are selective for xcex1vxcex23 over platelet fibrinogen receptor (xcex1IIbxcex23).
Integrin xcex1vxcex25 (Smith et al., J. Biol. Chem. 265:11008-13, 1990) is thought to be involved in endocytosis and degredation of vitronectin (J. Biol. Chem. 268:11492-5, 1993), cellular locomotion of human keratinocytes (J. Biol. Chem. 269:26926-32, 1994), tumor cell metastasis (J. Clin. Invest. 99:1390-1398, 1997), differentiation of neuroblastoma metastasis (Am. J. Pathol. 150:1631-1646, 1997), and viral infections (Nat. Med. (N.Y.) 5:78-82, 1999; J. Cell Biol. 127:257-64, 1994).
Integrin xcex1vxcex26 is an RGD, tenascin and fibronectin binding protein (J. Biol. Chem. 267:5790-6, 1992) which is expressed by a number of cells, such as carcinoma and epithelial cells, and is thought to be involved in carcinoma cell proliferation (J. Cell Biol. 127:547-56, 1994), in wound healing and cell attachment (J. Invest. Dermatol. 106:42-8, 1996), in epithelial inflammation, such as asthma (J. Cell Biol. 133:921-928, 1996), in inducing gelatinase B secretion, activation of the protein kinase-C pathway, tumor cell spreading and proliferation in colon cancer cells (Biochem. Biophys. Res. Commun. 249:287-291, 1998; Int. J. Cancer 81:90-97, 1999), in regulation of pulmonary inflammation and fibrosis and binding and activating transforming growth factor xcex21 (Munger et al., Cell (Cambridge, Mass.) 96:319-328, 1999), and in viral infections (Virology 239:71-77, 1997).
Antagonists of vitronectin receptors xcex1vxcex23, xcex1vxcex25 and/or xcex1vxcex26 have been reported to be useful in the treatment and prevention of atherosclerosis, restenosis, inflammation, wound healing, cancer (e.g., tumor regression by inducing apoptosis), metastasis, bone resorption related diseases (e.g., osteoporosis), diabetic retinopathy, macular degeneration, angiogenesis and viral disease (e.g., WO 99/30713; WO 99/30709).
WO 99/05107 discloses benzocycloheptenylacetic acid compounds useful as vitronectin receptor antagonists.
WO 98/14192 discloses benzazepin-3-on-4-ylacetic acid compounds as vitronectin receptor antagonists.
WO 96/26190 discloses benzodiazepine-3-one and benzazepin-3-one compounds as integrin receptor inhibitors.
WO 99/11626 discloses compounds of the formula 
wherein m, A, E, X1, X2, R2, R3, R4, R6and R7 are as defined therein, are useful as integrin receptor inhibitors, in particular fibrinogen (xcex1IIbxcex23) or vitronectin (xcex1vxcex23) receptor inhibitors.
WO 97/01540 discloses compounds of the formula 
wherein A1, E, X1, X2, X3, R2, R3, R4, R6 and R7 are as defined therein, are useful as integrin receptor inhibitors, in particular fibrinogen (xcex1IIbxcex23) or vitronectin (xcex1vxcex23) receptor inhibitors.
U.S. Pat. No. 5,565,449 discloses compounds of the formula 
wherein A, D, G, T, U, W and X are as defined therein, are useful as integrin inhibitors of fibrinogen GPIIbIIIa.
U.S. Pat. No. 5,705,890 discloses tricyclic benzodiazepine compounds useful as platelet aggregation (fibrinogen binding) inhibitors.
U.S. Pat. No. 5,674,865 discloses benzodiazepinedione compounds useful as platelet aggregation (fibrinogen binding) inhibitors.
WO 99/15178 and WO 99/15170 disclose benzazepineacetic acid compounds useful as vitronectin receptor antagonists.
WO 99/11626 and WO 99/06049 disclose tricyclic benzazepine, benzodiazepineacetate and benzazepineacetate compounds useful as fibrinogen and vitronectin receptor antagonists.
WO 99/15508 discloses dibenzo[a,d]cycloheptene-10-acetic acid compounds useful as vitronectin receptor antagonists.
WO 99/15506 and WO 99/15507 disclose iminobenzazulene compounds useful as vitronectin receptor antagonists.
WO 98/18461 discloses 4-10 membered mono- or polycyclic aromatic or nonaromatic ring system (containing 0-4 oxygen, sulfur and/or nitrogen heteroatoms) compounds useful as integrin receptor antagonists.
WO 97/01540 discloses dibenzocycloheptene compounds useful as integrin receptor antagonists.
WO 96/26190 discloses benzodiazepine-3-one and benzazepin-3-one compounds as integrin receptor inhibitors.
The present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as integrin receptors mediated diseases. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions mediated by integrin receptors, such as xcex1vxcex23, xcex1vxcex25, xcex1vxcex26 and the like. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of integrin receptors mediated diseases, such as cancer, tumor growth, metastasis, diabetic retinopathy, macular degeneration, angiogenesis, restenosis, bone resorption, atherosclerosis, inflammation, viral infection, wound healing and the like, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
The compounds of the invention are represented by the following general structure:
Exe2x80x94Bxe2x80x94(Alk)pxe2x80x94Qxe2x80x94(Alk)qxe2x80x94Axe2x80x94G
wherein E, B, Alk, Q, A, G, p and q are defined below.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their entirety.
The present invention provides novel compounds which are useful for treating disease states involving cancer, tumor growth, metastasis, diabetic retinopathy, macular degeneration, angiogenesis, restenosis, bone resorption, atherosclerosis, inflammation, viral disease, wound healing and the like, as well as other disease states associated with the same pathways effecting the noted disease states, especially those modulated by integrin receptors and related pathways, such as the integrin receptors xcex1vxcex23, xcex1vxcex25, xcex1vxcex26 and the like.
In accordance with the present invention, there is provided compounds of the formula:
Exe2x80x94Bxe2x80x94(Alk)pxe2x80x94Qxe2x80x94(Alk)qxe2x80x94Axe2x80x94G
or a pharmaceutically acceptable salt thereof, wherein p and q are each independently 0 or 1;
each Alk is independently an alkyl radical; preferably, a C1-C12 alkyl radical; more preferably, a C1-C8 alkyl radical; and most preferably, a C1-C6 alkyl radical;
A and Q each independently represent a bond, xe2x80x94C(X)xe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94N (R1)xe2x80x94 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, or a radical of cycloalkyl, aryl, heterocyclyl or heteroaryl each of which is optionally substituted by 1-3 radicals of R2;
preferably, A and Q each independently represent a bond, xe2x80x94C(X)xe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, or a radical of C3-C8 cycloalkyl, aryl, heterocyclyl of 5-8 ring members or heteroaryl of 5-10 ring members each of which is optionally substituted by 1-3 radicals of R2; and
more preferably, A and Q each independently represent a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94, or a radical of C3-C6 cycloalkyl, phenyl, heterocyclyl of 5-6 ring members or heteroaryl of 5-6 ring members each of which is optionally substituted by 1-3 radicals of R2; and
B represents a bond, xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, or a radical of cycloalkyl, aryl, heterocyclyl or heteroaryl each of which is optionally substituted by 1-3 radicals of R2;
preferably, B represents a bond, xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94, or a radical of C3-C8 cycloalkyl, aryl, heterocyclyl of 5-8 ring members or heteroaryl of 5-10 ring members each of which is optionally substituted by 1-3 radicals of R2;
more preferably, B represents a bond, xe2x80x94C(Y)xe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R1)xe2x80x94, or a radical of phenyl, heterocyclyl of 5-6 ring members or heteroaryl of 5-6 ring members each of which is optionally substituted by 1-3 radicals of R2; and
most preferably, B represents a bond, xe2x80x94S(O)txe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94N(R1)xe2x80x94, or a phenyl radical which is optionally substituted by 1-3 radicals of R2;
provided the total number of atoms that directly connect E to G via the shortest sequence is 3-12, preferably 4-9, more preferably 4-7;
each X is independently O or S; and preferably, O;
each Y is independently O, S, N(R1) or N(CN); and preferably, O, N(R1) or N(CN);
each t is independently 1 or 2; and preferably, 2;
each R1 is independently a hydrogen or alkyl radical; preferably, each R1 is independently a hydrogen or C1-C4 alkyl radical; and most preferably, each R1 is independently a hydrogen or methyl radical;
radicals of R2 are each independently a halo, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, hydroxy, carboxy, cyano, azido, amidino, guanidino, nitro, amino, alkylamino or dialkylamino radical or two adjacent R2 radicals represent a methylenedioxy, ethylenedioxy or propylenedioxy radical;
preferably, radicals of R2 are each independently a halo, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 haloalkoxy of 1-3 halo radicals, hydroxy, carboxy, cyano, azido, amidino, guanidino, nitro, amino, C1-C4 alkylamino or di(C1-C4 alkyl)amino radical or two adjacent R2 radicals represent a methylenedioxy, ethylenedioxy or propylenedioxy radical;
more preferably, radicals of R2 are each independently a halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylthio, xe2x80x94CF3, xe2x80x94OCF3, hydroxy, cyano, nitro, amino, C1-C4 alkylamino or di (C1-C4 alkyl)amino radical; and
most preferably, radicals of R2 are each independently a halo, methyl, methoxy, xe2x80x94CF3, xe2x80x94OCF3, hydroxy, cyano, nitro, amino, C1-C4 alkylamino or di (C1-C2 alkyl)amino radical;
E represents xe2x80x94R3, xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94R3, xe2x80x94C(Y)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94S(O)txe2x80x94R3, xe2x80x94S(O)txe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94Oxe2x80x94R3, xe2x80x94NHxe2x80x94S(O)txe2x80x94NHxe2x80x94R3, xe2x80x94NH-alkyl-C(Y)xe2x80x94R3, xe2x80x94NH-alkyl-S(O)txe2x80x94R3, xe2x80x94NH-alkyl-C(Y)xe2x80x94NHxe2x80x94R3 or xe2x80x94NH-alkyl-S(O)txe2x80x94NHxe2x80x94R3 radical;
preferably, E represents xe2x80x94R3, xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94R3, xe2x80x94C(Y)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94S(O)txe2x80x94R3, xe2x80x94S(O)txe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94Oxe2x80x94R3, xe2x80x94NHxe2x80x94S(O)txe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94(C1-C4 alkyl)-C(Y)xe2x80x94R3, xe2x80x94NHxe2x80x94(C1-C4 alkyl)-S(O)txe2x80x94R3, xe2x80x94NHxe2x80x94(C1-C4 alkyl)-C(Y)xe2x80x94NHxe2x80x94R3 or xe2x80x94NHxe2x80x94 (C1-C4 alkyl)-S(O)txe2x80x94NHxe2x80x94R3 radical;
more preferably, E represents xe2x80x94R3, xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94R3, xe2x80x94C(Y)xe2x80x94NHxe2x80x94R3, xe2x80x94S(O)txe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94Oxe2x80x94R3 or xe2x80x94NHxe2x80x94 (C1-C4 alkyl)-C(Y)xe2x80x94NHxe2x80x94R3 radical;
more preferably, E represents xe2x80x94R3, xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)xe2x80x94R3, xe2x80x94C(Y)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(Y)13 NHxe2x80x94R3 or xe2x80x94NHxe2x80x94C(Y)xe2x80x94Oxe2x80x94R3 radical; and
most preferably, E represents xe2x80x94R3, xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(NR1)xe2x80x94R1, xe2x80x94C(NR1)xe2x80x94NHxe2x80x94R1, xe2x80x94NHxe2x80x94C(NR1)xe2x80x94NHxe2x80x94R, or xe2x80x94NHxe2x80x94C (NR1)xe2x80x94Oxe2x80x94CH3 radical; or
alternatively preferably, E represents xe2x80x94NHxe2x80x94C(NR1)xe2x80x94R3, xe2x80x94C(NR1)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(NR1)xe2x80x94NHxe2x80x94R3 or a radical of the formula 
each of which formula is optionally substituted by 1-2 radicals of R2; wherein n is 1-4, preferably, 1-3; more preferably, 1-2; and
more preferably, E represents xe2x80x94NHxe2x80x94C(NR1)xe2x80x94R3, xe2x80x94C(NR1)xe2x80x94NHxe2x80x94R3, xe2x80x94NHxe2x80x94C(NR1)xe2x80x94NHxe2x80x94R3 or a radical of the formula 
each of which formula is optionally substituted by 1-2 radicals of R2;
R3 is a radical of hydrogen, alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl or heterocyclyl-alkyl, wherein the aryl, heteroaryl and heterocyclyl radicals are optionally substituted by 1-3 radicals of R2;
preferably, R3 is hydrogen, C1-C10 alkyl, aryl, aryl-C1-C10 alkyl, heteroaryl, heteroaryl-C1-C10 alkyl, heterocyclyl or heterocyclyl-C1-C10 alkyl radical, wherein the heteroaryl and heterocyclyl radicals have 5-15 ring members and the aryl, heteroaryl and heterocyclyl radicals are optionally substituted by 1-3 radicals of R2;
more preferably, R3 is hydrogen, C1-C4 alkyl, aryl, aryl-C1-C4 alkyl, heteroaryl, heteroaryl-C1-C4 alkyl, heterocyclyl or heterocyclyl-C1-C4 alkyl radical, wherein the heteroaryl and heterocyclyl radicals have 5-15 ring members and the aryl, heteroaryl and heterocyclyl radicals are optionally substituted by 1-3 radicals of R2;
more preferably, R3 is hydrogen, C1-C4 alkyl, aryl, aryl-C1-C4 alkyl, heteroaryl or heteroaryl-C1-C4 alkyl radical, wherein the heteroaryl radical has 5-15 ring members and the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of R2;
more preferably, R3 is a heteroaryl radical of 5-15 ring members and is optionally substituted by 1-3 radicals of R2;
most preferably, R3 is a heteroaryl radical of 5-10 ring members and is optionally substituted by 1-3 radicals of R2;
G is a radical of formula 
preferably, G is a radical of formula 
more preferably, G is a radical of formula 
alternatively more preferably, G is a radical of formula 
alternatively more preferably, G is a radical of formula 
W1 is Cxe2x80x94R15 or N; W2 is Cxe2x80x94R16 or N; W3 is Cxe2x80x94R17 or N; and W4 is Cxe2x80x94R18 or N; or W1 and W2, W2 and W3, or W3 and W4 taken together represent a fused phenyl, fused C5-C7 cycloalkyl, fused heteroaryl of 5-6 ring members or fused heterocyclyl of 5-7 ring members, each of which is optionally substituted by 1-3 radicals of R2; preferably, W1 is Cxe2x80x94R15 or N; W2 is Cxe2x80x94R16 or N; W3 is Cxe2x80x94R17 or N; and W4 is Cxe2x80x94R18 or N; and more preferably, W1 is Cxe2x80x94R15; W2 is Cxe2x80x94R16; W3 is Cxe2x80x94R17; and W4 is Cxe2x80x94R18; provided not more than 2 of W1, W2, W3 or W4 represent N; preferably, not more than 2 of W1, W2, W3 or W4 represent N;
radicals of R15, R17 and R18 are each independently a radical of hydrogen, halo, hydroxy, carboxy, cyano, azido, amidino, nitro, amino, xe2x80x94R9, xe2x80x94C(Y)xe2x80x94R9, xe2x80x94S(O)txe2x80x94R9, xe2x80x94Sxe2x80x94R9, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R1)xe2x80x94R9, xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94H, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94R9, xe2x80x94Oxe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94Oxe2x80x94R9, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94R9or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9;
preferably, radicals of R15, R17 and R18 are each independently a radical of hydrogen, halo, hydroxy, carboxy, cyano, azido, amidino, nitro, amino, xe2x80x94R9, xe2x80x94C(O)xe2x80x94R9, xe2x80x94S(O)txe2x80x94R9, xe2x80x94Sxe2x80x94R9, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R1)xe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94H, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94R9, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94R9;
more preferably, radicals of R15, R17 and R18 are each independently a radical of hydrogen, halo, hydroxy, cyano, C1-C3 alkyl, C1C3 alkoxy, xe2x80x94CF3 or xe2x80x94OCF3; and
most preferably, R15, R17 and R18 are each independently a radical of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, methyl, methoxy, xe2x80x94CF3 or xe2x80x94OCF3; and
R16 is a radical of hydrogen, halo, hydroxy, carboxy, cyano, azido, amidino, nitro, amino, xe2x80x94R9, xe2x80x94C(Y)xe2x80x94R9, xe2x80x94S(O)txe2x80x94R9, xe2x80x94Sxe2x80x94R9, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R1)xe2x80x94R9, xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94H, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94R9, xe2x80x94Oxe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94Oxe2x80x94R9, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94R9 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9;
preferably, R16 is a radical of hydrogen, halo, hydroxy, carboxy, cyano, azido, amidino, nitro, amino, xe2x80x94R9, xe2x80x94C(O)xe2x80x94R9, xe2x80x94S(O)txe2x80x94R9, xe2x80x94Sxe2x80x94R9, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R1)xe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94H, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94R9, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9or xe2x80x94N (R1)xe2x80x94S(O)txe2x80x94R9;
more preferably, R16 is a radical of hydrogen, halo, hydroxy, carboxy, cyano, amino, xe2x80x94R9, xe2x80x94S(O)txe2x80x94R9, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R1)xe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94H, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94R9, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9 or xe2x80x94N(R1xe2x80x94S(O)txe2x80x94R9; and
most preferably, R16 is a radical of hydrogen, fluoro, chloro, bromo, hydroxy, cyano, amino, xe2x80x94R9, xe2x80x94S(O)txe2x80x94R9, xe2x80x94Oxe2x80x94R9, xe2x80x94N(R1)xe2x80x94R9, xe2x80x94C(O)xe2x80x94N(R1)xe2x80x94R9, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94H, xe2x80x94N(R1)xe2x80x94C(O)xe2x80x94R9, xe2x80x94S(O)txe2x80x94N(R1)xe2x80x94R9 or xe2x80x94N(R1)xe2x80x94S(O)txe2x80x94R9; or
alternatively, R15 and R16, R16 and R17, or R17 and R18 taken together represent a methylenedioxy, ethylenedioxy or propylenedioxy radical; and
provided the combined total number of aryl, cycloalkyl, heteroaryl and heterocyclyl radicals in R15, R16, R17 and R18 is 0-1;
wherein each R9 is independently a radical of alkyl, haloalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl radicals are optionally substituted by 1-3 radicals of R2;
preferably, each R9 is independently a radical of C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, arylxe2x80x94C1-C4 alkyl, heteroarylxe2x80x94C3-C4 alkyl, heterocyclyl-C1-C4 alkyl, aryl, cycloalkyl, heteroaryl or heterocyclyl, wherein the aryl, cycloalkyl, heteroaryl and heterocyclyl radicals are optionally substituted by 1-3 radicals of R2;
more preferably, each R9 is independently a radical of C1-C4 alkyl, xe2x80x94CF3, phenyl-C1-C4 alkyl or phenyl, wherein each phenyl radical is optionally substituted by 1-3 radicals of R2; and
most preferably, each R9 is independently a radical of C1-C4 alkyl, xe2x80x94CF3, phenyl-Cl-C2 alkyl or phenyl, wherein each phenyl radical is optionally substituted by 1-3 radicals of R2;
X2, X3 and X6 are each independently a xe2x80x94C(X)xe2x80x94, xe2x80x94S(O)txe2x80x94, xe2x80x94CHR6xe2x80x94 or xe2x80x94CHR7xe2x80x94 radical; preferably, X2, X3 and X6 are each independently a xe2x80x94CHR6xe2x80x94 or xe2x80x94CHR7xe2x80x94 radical; and more preferably X2, X3 and X6 are each independently a xe2x80x94CHR6xe2x80x94 radical;
Z1 is N or Cxe2x80x94R6; preferably, Z1 is Cxe2x80x94R6;
R10 and R12 are each independently an xe2x80x94R6, xe2x80x94R7 or xe2x80x94OR7 radical; preferably, R10 and R12 are each independently a hydrogen, hydroxy or C1-C4 alkyl radical; more preferably, R10 and R12 are each independently a hydrogen, hydroxy or C1-C2 alkyl radical; most preferably, R10 and R12 are each a hydrogen radical;
provided the combined total number of aryl, heteroaryl and heterocyclyl radicals in X2, X3, X6, R10 and R12 is 0-2; preferably, 0-1;
wherein each R6 is independently a hydrogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, halo or cyano radical; preferably, each R6 is independently a hydrogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl of 1-3 halo radicals, C1-C4 alkoxy, C1-C4 haloalkoxy, halo or cyano radical; more preferably, each R6 is independently a hydrogen, hydroxy or C1-C2 alkyl radical; and most preferably, each R6 is a hydrogen radical; and
each R7 is independently a radical of aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl or heterocyclyl-alkyl, each of which is optionally substituted by 1-3 radicals of R2; preferably, each R7 is independently a radical of aryl, aryl-C1-C4 alkyl, heteroaryl, heteroaryl-C1-C4 alkyl, heterocyclyl or heterocyclyl-C1-C4 alkyl, each of which is optionally substituted by 1-3 radicals of R2, and wherein the heteroaryl and heterocyclyl radicals have 5-10 ring members; more preferably, each R7 is independently a radical of phenyl, phenyl-C1-C2 alkyl, heteroaryl, heteroaryl-C1-C2 alkyl, heterocyclyl or heterocyclyl-C1-C2 alkyl, each of which is optionally substituted by 1-3 radicals of R2, and wherein the heteroaryl and heterocyclyl radicals have 5-6 ring members; and
R4 is an alkyl radical substituted by a radical of carboxy, tetrazolyl, xe2x80x94CO2R8, xe2x80x94C(O)xe2x80x94NHxe2x80x94S(O)txe2x80x94R8, xe2x80x94C(O)xe2x80x94NHxe2x80x94C(O)xe2x80x94R6 or xe2x80x94C(O)xe2x80x94NHxe2x80x94R8, and optionally substituted by a radical of aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1-3 radicals of R2;
preferably, R4 is a C1-C10 alkyl radical substituted by a radical of carboxy, tetrazolyl, xe2x80x94CO2R8, xe2x80x94C(O)xe2x80x94NHxe2x80x94S(O)txe2x80x94R8, xe2x80x94C(O)xe2x80x94NHxe2x80x94C(O)xe2x80x94R8 or xe2x80x94C(O)xe2x80x94NHxe2x80x94R8, and optionally substituted by a radical of aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1-3 radicals of R2;
more preferably, R4 is a C1-C4 alkyl radical substituted by a radical of carboxy, tetrazolyl, or xe2x80x94CO2R8, and optionally substituted by a radical of aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1-3 radicals of R2;
more preferably, R4 is a C1-C4 alkyl radical substituted by a radical of carboxy or xe2x80x94CO2R8; and most preferably, R4 is a C1-C2 alkyl radical substituted by a radical of carboxy or xe2x80x94CO2R8;
wherein R8 is an alkyl radical substituted by 1-2 radicals of hydroxy, carboxy, amino, aryl or heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of R2;
preferably, R8 is a C1-C10 alkyl radical substituted by 1-2 radicals of hydroxy, carboxy, amino, aryl or heteroaryl of 5-10 ring members, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of R2;
more preferably, R8 is a C1-C4 alkyl radical optionally substituted by a radical of aryl or heteroaryl of 5-10 ring members, wherein the aryl and heteroaryl radicals are optionally substituted by 1-3 radicals of R2;
more preferably, R8 is a C1-C4 alkyl radical optionally substituted by a phenyl radical, wherein the phenyl radical is optionally substituted by 1-3 radicals of R2; and most preferably, R8 is a C1-C2 alkyl radical.
In another aspect of the invention, there is provided a method for the therapeutic or prophylactic treatment of disease states involving tumor growth, metastasis, diabetic retinopathy, macular degeneration, angiogenesis, restenosis, bone resorption, atherosclerosis, inflammation, viral disease, wound healing or the like in a warm-blooded animal which comprises administering to a warm blooded animal in need thereof a therapeutically or prophylactically effective amount of a compound or pharmacutical composition of the invention.
In a further embodiment of the invention, there is provided a method for modulation, preferably inhibition, of one or more integrin receptors which comprises administering to a warm blooded animal in need thereof an effective amount of a compound or pharmacutical composition of the invention.
In a further embodiment of the invention, there is provided a method for modulation, preferably inhibition, of one or more vitronectin receptors which comprises administering to a warm blooded animal in need thereof an effective amount of a compound or pharmacutical composition of the invention.
In a related embodiment, there is provided a method for modulation, preferably inhibition, of xcex1vxcex23 and/or xcex1vxcex25 and/or xcex1vxcex2≢receptors which comprises administering to a warm blooded animal in need thereof an effective amount of a compound or pharmacutical composition of the invention.
An additionally preferred embodiment of the invention includes a method for the therapeutic or prophylactic treatment of an integrin receptor mediated disease state in a warm-blooded animal which comprises administering to said animal a therapeutically or prophylactically effective amount of a compound or pharmacutical composition of the invention. For example, the compounds of the invention may modulate an integrin receptor mediated response, for example, by antagonizing one or more vitronectin receptors response. Especially preferred in this embodiment is the inhibition of the xcex1vxcex23 and/or xcex1vxcex25 and/or xcex1vxcex26 receptor response.
The compounds and pharmacutical compositions of this invention are useful in the prophylaxis and/or treatment (comprising administering to a warm blooded animal, such as a mammal (e.g., a human, horse, sheep, pig, mouse, rat, bovine and the like) an effective amount of such compound or composition) of (1) diseases and disorders which can be effected or facilitated by modulating one or more integrin receptors, such as by antagonizing one or more integrin receptors, including but not limited to disorders induced or facilitated by one or more integrin receptors; (2) diseases and disorders which can be effected or facilitated by modulating one or more vitronectin receptors, such as by antagonizing one or more vitronectin receptors, including but not limited to disorders induced or facilitated by one or more vitronectin receptors; (3) diseases and disorders which can be effected or facilitated by modulating the xcex1vxcex23 and/or xcex1vxcex25 and/or xcex1vxcex26 receptor response, such as by inhibition of the xcex1vxcex23 and/or xcex1vxcex25 and/or xcex1vxcex26 receptor response, including but not limited to disorders induced or facilitated by the xcex1vxcex23 and/or xcex1vxcex25 and/or xcex1vxcex26 receptor response; or (4) disease states involving cancer, such as tumor growth; metastasis; diabetic retinopathy; macular degeneration; angiogenesis; restenosis; bone resorption, such as osteoporosis, osteoarthritis, bone formation, bone loss, hyperparathyroidism, Paget""s disease, hypercalcemia of malignancy, osteolytic lesions, In Behcet""s disease, osteomalacia, hyperostosis or osteopetrosis; atherosclerosis; inflammation, such as rheumatoid arthritis, pain, psoriasis or allergies; viral disease; wound healing; or the like.
As utilized herein, the following terms shall have the following meanings:
xe2x80x9cAlkylxe2x80x9d, alone or in combination, means a saturated or partially unsaturated (provided there are at least two carbon atoms) straight-chain or branched-chain alkyl radical containing the designated number of carbon atoms; preferably 1-18 carbon atoms (C1-C18), more preferably 1-12 carbon atoms (C1-C12), more preferably 1-8 carbon atoms (C1-C8), more preferably 1-6 carbon atoms (C1-C6), more preferably 1-4 carbon atoms (C1-C4), more preferably 1-3 carbon atoms (C1-C3), and most preferably 1-2 carbon atoms (C1-C2). Examples of such radicals include methyl, ethyl, vinyl, n-propyl, allyl, isopropyl, n-butyl, 1-butenyl, 2-butenyl, 3-butenyl, sec-butyl, sec-butenyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbutenyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and the like. A partially unsaturated alkyl preferably has at least one double or triple bond, more preferably 1-3 double or triple bonds , more preferably 1-2 double or triple bonds, and most preferably 1 double bond or 1 triple bond. xe2x80x9cAlkylxe2x80x9d may also represent a divalent alkyl radical, such as aryl-alkyl-.
xe2x80x9cAlkoxyxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Oxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cOxe2x80x9d is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, allyloxy and the like.
xe2x80x9cAlkylthioxe2x80x9d, alone or in combination, means a radical of the type xe2x80x9cRxe2x80x94Sxe2x80x94xe2x80x9d wherein xe2x80x9cRxe2x80x9d is an alkyl radical as defined above and xe2x80x9cSxe2x80x9d is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, allylthio and the like.
The term xe2x80x9ccarbocyclicxe2x80x9d, alone or in combination, refers to an organic cyclic moiety in which the cyclic skeleton is comprised of only carbon atoms whereas the term xe2x80x9cheterocyclicxe2x80x9d, alone or in combination, refers to an organic cyclic moiety in which the cyclic skeleton contains one or more, preferably 1-4, more preferably 1-3, most preferably 1-2, heteroatoms selected from nitrogen, oxygen, or sulfur and which may or may not include carbon atoms.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, refers to a saturated or partially unsaturated (preferably 1-2 double bonds, more preferably 1 double bond) carbocyclic moiety containing the indicated number of carbon atoms, preferably 3-12 ring members, more preferably 3-8 ring members, and most preferably, 3-6 ring members. For example, the term xe2x80x9cC3-C10 cycloalkylxe2x80x9d refers to an organic cyclic substituent in which three to ten carbon atoms form a three, four, five, six, seven, eight, nine or ten-membered ring, including, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cyclohexyl, cycloheptyl, cyclooctyl and the like ring. As used herein, xe2x80x9ccycloalkylxe2x80x9d may also refer to two or more cyclic ring systems which are fused to form, for example, bicyclic, tricyclic, or other similar bridged compounds (e.g. norbornanyl, norbornenyl, adamantanyl, etc.).
xe2x80x9cArylxe2x80x9d refers to an aromatic carbocyclic group having a single ring, for example, a phenyl ring, multiple rings, for example, biphenyl, or multiple condensed rings in which at least one ring is aromatic, for example, naphthyl, 1,2,3,4,-tetrahydronaphthyl, anthryl, or phenanthryl, which can be unsubstituted or substituted with one or more (preferably 1-5, more preferably 1-4, more preferably 1-3, most preferably 1-2) other substituents as defined above. The substituents attached to a phenyl ring portion of an aryl moiety in the compounds of this invention may be configured in the ortho-, meta- or para-orientations. Examples of typical aryl moieties included in the scope of the present invention may include, but are not limited to, the following: 
xe2x80x9cAryl-alkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above wherein a hydrogen radical is replaced with an aryl radical, such as benzyl, and for example, xe2x80x9caryl-C1-C4 alkylxe2x80x9d, alone or in combination, means a C1-C4 alkyl radical as defined above wherein a hydrogen radical is replaced with an aryl radical.
xe2x80x9cHeterocyclexe2x80x9d refers to a saturated, unsaturated or aromatic carbocyclic group having a single ring, multiple rings or multiple condensed rings, and having at least one hetero atom such as nitrogen, oxygen or sulfur within at least one of the rings. xe2x80x9cHeteroarylxe2x80x9d refers to a heterocycle in which at least one ring is aromatic. Further, bi- or tri-cyclic heteroaryl moieties may comprise at least one ring which is either completely or partially saturated. Any of the heteroaryl groups can be unsubstituted or optionally substituted with one or more groups as defined above and one or more, preferably 1-2, more preferably one, xe2x80x9coxoxe2x80x9d group. xe2x80x9cHeterocyclylxe2x80x9d refers to a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably monocyclic, heterocycle radical containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, nitrogen, oxygen or sulfur atom ring member and having preferably 3-8 ring members in each ring, more preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. xe2x80x9cHeterocyclylxe2x80x9d is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic fused, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms. Any of the heterocyclyl groups can be unsubstituted or optionally substituted with one or more groups as defined above and one or more, preferably 1-2, more preferably one, xe2x80x9coxoxe2x80x9d group.
As one skilled in the art will appreciate such heterocycle moieties may exist in several isomeric forms, all of which are to be encompassed by the present invention. For example, a 1,3,5-triazine moiety is isomeric to a 1,2,4-triazine group. Such positional isomers are to be considered within the scope of the present invention. Likewise, the heterocyclyl or heteroaryl groups can be bonded to other moieties in the compounds of the invention. The point(s) of attachment to these other moieties is not to be construed as limiting on the scope of the invention. Thus, by way of example, a pyridyl moiety may be bound to other groups through the 2-, 3-, or 4-position of the pyridyl group and a piperidinyl may be bound to other groups through the nitogen or carbon atoms of the piperidinyl group. All such configurations are to be construed as within the scope of the present invention.
Examples of heterocyclic or heteroaryl moieties included in the scope of the present invention may include, but are not limited to, the following: 
Heterocycle xe2x80x9cfusedxe2x80x9d forms a ring system in which a heterocyclyl or heteroaryl group and a cycloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.
xe2x80x9cBenzoxe2x80x9d, alone or in combination, means the divalent radical C6H4=derived from benzene. xe2x80x9cBenzo fusedxe2x80x9d forms a ring system in which benzene and a cycloalkyl or aryl group have two carbons in common, for example tetrahydronaphthylene and the like.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to a halogen atom which may include fluoro, chloro, bromo and iodo. Preferred halo groups include chloro, bromo and fluoro with chloro and fluoro being especially preferred.
xe2x80x9cHaloalkylxe2x80x9d, alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis(trifluoromethyl)methyl and the like.
The following table defines by example certain ring structure abbreviations used herein:
Certain symbols used herein are indended to have the following meanings: 
It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups (Yxe2x80x2=O, S, NR), and the like 
and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim.
xe2x80x9cModulatexe2x80x9d as used herein refers to the ability of a compound of this invention to interact with a receptor, target gene or other gene product to (a) up-regulate the activity of that receptor, target gene or other gene product or biological effect (for example, as an agonist) or (b) down-regulating the receptor, target gene or other gene product or other biological effect, particularly by acting as an antagonist for the receptor, target gene or other gene product. Additionally, encompassed by xe2x80x9cmodulatexe2x80x9d is the ability of a compound of the invention to effect a desired biological response, even if that response occurs upstream or downstream one or more steps in a signaling pathway from the receptor, target gene or other gene product in question. Thus, by way of example, the compounds of the invention may provide the desired effect by interacting with an integrin receptor, particularly a vitronectin receptor, such as the xcex1vxcex23 and/or xcex1vxcex25 and/or xcex1vxcex26 receptor, to act as an agonist or antagonist to that receptor or at some point, either upstream or downstream, in the signaling pathway for the receptor to effect the desired therapeutic or prophylactic response.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d, as used herein, refers to an organic or inorganic salt which is useful in the treatment of a warm-blooded animal. Such salts can be acid or basic addition salts, depending on the nature of the compound of this invention. For examples of xe2x80x9cpharmacologically acceptable salts,xe2x80x9d see Berge et al., J. Pharm. Sci. 66:1 (1977). As used herein, xe2x80x9cwarm blooded animalxe2x80x9d includes a mammal, including a member of the human, equine, porcine, bovine, murine, canine, feline and the like species.
In the case of an acidic moiety in a compound of this invention, a salt may be formed by treatment of a compound of this invention with a basic compound, particularly an inorganic base. Preferred inorganic salts are those formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Preferred organic base salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine, dibenzyl-ethylenediamine, and the like salts. Other salts of acidic moieties may include, for example, those salts formed with procaine, quinine and N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. An especially preferred salt is a sodium or potassium salt of a compound of this invention.
With respect to basic moieties, a salt is formed by the treatment of a compound of this invention with an acidic compound, particularly an inorganic acid. Preferred inorganic salts of this type may include, for example, the hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric or the like salts. Preferred organic salts of this type, may include, for example, salts formed with formic, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, d-glutamic, d-camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, para-toluenesulfonic, sorbic, puric, benzoic, cinnamic and the like organic acids. An especially preferred salt of this type is a hydrochloride or sulfate salt of a compound of this invention.
Also encompassed in the scope of the present invention are pharmaceutically acceptable esters of a carboxylic acid or hydroxyl containing group, including a metabolically labile ester or a prodrug form of a compound of this invention. A metabolically labile ester is one which may produce, for example, an increase in blood levels and prolong the efficacy of the corresponding non-esterified form of the compound. A prodrug form is one which is not in an active form of the molecule as administered but which becomes therapeutically active after some in vivo activity or biotransformation, such as metabolism, for example, enzymatic or hydrolytic cleavage. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acid prodrugs, their preparation and use. Esters of a compound of this invention, may include, for example, the methyl, ethyl, propyl, and butyl esters, as well as other suitable esters formed between an acidic moiety and a hydroxyl containing moiety. Metabolically labile esters, may include, for example, methoxymethyl, ethoxymethyl, iso-propoxymethyl, xcex1-methoxyethyl, groups such as xcex1-((C1-C4)alkyloxy)ethyl; for example, methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.; 2-oxo-1,3-dioxolen-4-ylmethyl groups, such as 5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C1-C3 alkylthiomethyl groups, for example, methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups, for example, pivaloyloxymethyl, xcex1-acetoxymethyl, etc.; ethoxycarbonyl-1-methyl; or xcex1-acyloxy-xcex1-substituted methyl groups, for example xcex1-acetoxyethyl.
Additionally, the compounds of the invention may have one or more asymmetric carbon atoms and, therefore, may exist in stereoisomeric forms. All stereoisomers are intended to be included within the scope of the present invention. As used, xe2x80x9cstereoisomerxe2x80x9d or xe2x80x9cstereoisomericxe2x80x9d refers to a compound which has the same molecular weight, chemical composition, and constitution as another, but with the atoms grouped such that their orientation in three-dimensional space is different. Such stereoisomers may exist as enantiomeric mixtures, diastereomers or may be resolved into individual stereoisomeric components (e.g. specific enantiomers) by methods familiar to one skilled in the art.
Likewise, the compounds of this invention may exist as isomers, that is compounds of the same molecular formula but in which the atoms, relative to one another, are arranged differently. One skilled in the art will appreciate that it is possible to prepare compounds of this invention in which one or more of the substituents are reversed in orientation relative to the other atoms in the molecule. That is, the substituent to be inserted may be the same as that noted except that it is inserted into the molecule in the reverse orientation. One skilled in the art will appreciate that these isomeric forms of the compounds of this invention are to be construed as encompassed within the scope of the present invention.
Further, the compounds of the invention may exist as crystalline solids which can be crystallized from common solvents such as ethanol, N,N-dimethyl-formamide, water, or the like. Thus, crystalline forms of the compounds of the invention may exist as solvates and/or hydrates of the parent compounds or their pharmaceutically acceptable salts. All of such forms likewise are to be construed as falling within the scope of the invention.
While it may be possible to administer a compound of the invention alone, in the methods described, the compound administered normally will be present as an active ingredient in a pharmaceutical formulation. Thus, in one another embodiment of the invention, there is provided a formulation comprising a compound of this invention in combination with a pharmaceutically acceptable carrier, diluent or excipient therefor.
The composition used in the noted therapeutic methods can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. The preferred form depends on the intended mode of administration and therapeutic application. Considerations for preparing appropriate formulations will be familiar to one skilled in the art and are described, for example, in Goodman and Gilman""s: xe2x80x9cThe Pharmacological Basis of Therapeuticsxe2x80x9d, 8th Ed., Pergamon Press, Gilman et al. eds. (1990); and xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d, 18th Ed., Mack Publishing Co., A. Gennaro, ed. (1990). Methods for administration are discussed therein, e.g. for oral, topical, intravenous, intraperitoneal, or intramuscular administration. Pharmaceutically acceptable carriers, diluents, and excipients, likewise, are discussed therein. Typical carriers, diluents, and excipients may include water (for example, water for injection), buffers, lactose, starch, sucrose, and the like.
As noted, a compound of the invention can be administered orally, topically or parenterally (e.g. intravenously, intraperitoneally, intramuscularly, subcutaneously, etc.), or inhaled as a dry powder, aerosol, or mist, for pulmonary delivery. Such forms of the compounds of the invention may be administered by conventional means for creating aerosols or administering dry powder medications using devices such as for example, metered dose inhalers, nasal sprayers, dry powder inhaler, jet nebulizers, or ultrasonic nebulizers. Such devices optionally may be include a mouthpiece fitted around an orifice. In certain circumstances, it may be desirable to administer the desired compound of the invention by continuous infusion, such as through a continuous infusion pump, or using a transdermal delivery device, such as a patch.
The compounds of the invention may also be administered as an aerosol. The term xe2x80x9caerosolxe2x80x9d includes any gas-borne suspended phase of a compound of the invention which is capable of being inhaled into the bronchioles or nasal passages. Specifically, aerosol includes a gas-borne suspension of droplets of the desired compound, as may be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition of a compound of the instant invention suspended in air or other carrier gas, which may be delivered by insufflation from an inhaler device, for example.
For solutions used in making aerosols of the invention, the preferred range of concentration of the compounds of the invention is 0.1-100 milligrams (mg)/milliliter (mL), more preferably 0.1-30 mg/mL, and most preferably 1-10 mg/mL. Usually the solutions are buffered with a physiologically compatible buffer such as phosphate or bicarbonate. The usual pH range is from about 5 to about 9, preferably from about 6.5 to about 7.8, and more preferably from about 7.0 to about 7.6. Typically, sodium chloride is added to adjust the osmolarity to the physiological range, preferably within 10% of isotonic. Formulation of such solutions for creating aerosol inhalants is discussed, for example, in Remington""s, supra; See, also, Ganderton and Johens, xe2x80x9cDrug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda, xe2x80x9cCritical Review in Therapeutic Drug Carrier Systemsxe2x80x9d 6 273-313 (1990); and Raeburn et al. J. Pharmacol. Toxicol. Methods. 27 143-159 (1992).
Solutions of a compound of the invention may be converted into aerosols by any of the known means routinely used for making aerosol inhalant pharmaceuticals. In general, such methods comprise pressurizing or providing a means of pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice, thereby pulling droplets of the solution into the mouth and trachea of the animal to which the drug is to be administered. Typically, a mouthpiece is fitted to the outlet of the orifice to facilitate delivery into the mouth and trachea.
In one embodiment, devices of the present invention comprise solutions of the compounds of the invention connected to or contained within any of the conventional means for creating aerosols in asthma medication, such as metered dose inhalers, jet nebulizers, or ultrasonic nebulizers. Optionally such devices may include a mouthpiece fitted around the orifice.
Further, there are provided a device which may comprise a solution of a compound of the instant invention in a nasal sprayer.
A dry powder comprising a compound of the invention, optionally with an excipient is another embodiment. This may be administered by a drug powder inhaler containing the described powder.
Powders may be formed with the aid of any suitable powder bases, for example, talc, lactose, starch and the like. Drops may be formulated with an aqueous base or non-aqueous base also comprising one or more dispersing agents, suspending agents solubilizing agents, and the like.
Any of the formulations of the invention may also include one or more preservatives or bacteriostatic agents, for example, methyl hydroxybenzoate, ethyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chlorides, and the like. Additionally, the formulations may contain other active ingredients.
The pharmaceutical formulations of the invention may be administered by parenteral or oral administration for prophylactic and/or therapeutic treatment. The pharmaceutical compositions can be administered in a variety of unit dosage forms depending on the method of administration. For example, unit dosage forms suitable for oral administration may include, powders, tablets, pills, capsules and dragees.
The pharmaceutical formulations can be administered intravenously. Therefore, the invention further provides formulations for intravenous administration which comprise a compound of the invention dissolved or suspended in a pharmaceutically acceptable carrier or diluent therefor. A variety of aqueous carriers can be used, for example, water, buffered water or other buffer solutions, saline, and the like. The resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The sterile aqueous solution for the lyophilized product can be packaged as a kit for use with the lyophilized formulation. The compositions can contain pharmaceutically acceptable substances to aid in administration and more closely mimic physiological conditions. Such substances, can include, for example, pH adjusting substances such as acids, bases or buffering agents, tonicity adjusting agents, wetting agents and the like. Such substances may include but are not limited to, for example, sodium hydroxide, hydrochloric acid, sulfuric acid, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, and the like or any other means familiar to one skilled in the art for maintaining pH at a desired level.
For solid formulations, carriers, diluents, and excipients known to one skilled in the art may be used. Such carriers, diluents and excipients may include, for example, mannitol, lactose, starch magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, or other solid polyol sugar, magnesium carbonate, and the like. For oral administration, a pharmaceutically acceptable formulation is prepared by admixing any of the usual carrier, diluents, and excipients, such as those noted, with from about 0.1 to about 95% of a compound of the invention.
The preferred dosage for use in the methods of the invention, however, is in the range of about 0.01 mg/kg to about 100 mg/kg of body weight, preferably from about 0.1 mg/kg to about 50 mg/kg, up to 4 times per day. Whatever the dosage form, one skilled in the art will recognize that the dosage administered will be adjusted to factors such as the age, weight, and condition of the patient involved. The skilled practitioner will be familiar with how to adjust the dosage to accommodate these and other factors.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, the compounds can also be used in combination with one or more agents such as anti-platelet agents, anti-inflammatory agents, matrix metalloproteinase inhibitors, cancer treatment agents, antiinfective agents and the like. For example, the compounds of the invention can be administered in combination with glycoprotein IIb/IIIa receptor antagonists for the prophylaxis and/or treatment of acute coronary ischemic syndrome and the like (WO 97/35615, incorporated herein by reference in its entirety), or in combination with IL-1 antagonists, such as, p38 inhibitors, TNF-xcex1 inhibitors, IL-1 inhibitors, IL-1 receptor antagonist (IL-1Ra) and the like, for the prophylaxis and/or treatment of rheumatoid arthritis, osteoarthritis and the like (Arner et al., Arthritis and Rheumatism 38:1304-14, 1995). When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
Compound Synthesis
Compounds of the invention can be synthesized according to one or more of the following methods. It should be noted that the general procedures are shown as it relates to preparation of compounds having unspecified stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, e.g., where the stereochemistry about a group is (S) or (R). In addition, the compounds having one stereochemistry (e.g., (R)) can often be utilized to produce those having opposite stereochemistry (i.e., (S)) using well-known methods, for example, by inversion. Because compounds of the invention can possess one or more asymmetric carbon atoms, the compounds are thus capable of existing in the form of optical isomers as well as in the form of racemic or nonracemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example by formation of diastereoisomeric salts by treatment with an optically active acid or base. Examples of appropriate acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, camphorsulfonic acid and the like. Examples of appropriate bases are brucine, ephedrine, strychnine, morphine and the like. The separation of the mixture of diastereoisomers by crystallization is followed by liberation of the optically active bases from these salts. A alternative process for separation of optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Another available method involves synthesis of covalent diastereoisomeric molecules by reacting compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. The optically active compounds of the invention can likewise be obtained by utilizing optically active starting materials or alternatively, by generating optically active synthetic intermediates either by chiral reactions, such as using a chiral reagent, chiral catalyst and the like, or by isolating the desired chiral synthetic intermediate isomer using the methods described above. These isomers may be in the form of a free acid, a free base, an ester or a salt.
xe2x80x9cLeaving groupxe2x80x9d (L) generally refers to groups readily displaceable by a nucleophile, such as an amine, a carbon, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
xe2x80x9cProtecting groupxe2x80x9d generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like (see Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, Wiley, 1991). Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and nmercapto groups. For example, aralkyl groups. Alkyl groups are also sutiable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups ainclude, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-tri-silyl derivative. Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium flouride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxy carbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoro-acetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydroylsis and hydrogenolysis conditions well known to those skilled in the art.
Compounds of the invention may be prepared as described in the following schemes and synthetic examples.
Compounds of the invention, Exe2x80x94B-(Alk)p-Q-(Alk)q-Axe2x80x94G, can be prepared by one or more of the following coupling reactions using reagents, reaction conditions and solvents typical for such coupling reactions:
1. E+L-(Alk)p-Q-(Alk)q-Axe2x80x94G
2. Exe2x80x94OH+L-(Alk)p-Q-(Alk)q-Axe2x80x94G
3. Exe2x80x94SH+L-(Alk)p-Q-(Alk)q-Axe2x80x94G
4. Exe2x80x94NHR1+L-(Alk)p-Q-(Alk)q-Axe2x80x94G
5. Exe2x80x94NHR1+Lxe2x80x94C(Y)-(Alk)p-Q-(Alk)q-Axe2x80x94G
6. Exe2x80x94NHR1+Lxe2x80x94C(Y)-NR1-(Alk)p-Q-(Alk)q-Axe2x80x94G
7. Exe2x80x94NHR1+Lxe2x80x94S(O)t-(Alk)p-Q-(Alk)q-Axe2x80x94G
8. Exe2x80x94NHR1+Lxe2x80x94S(O)txe2x80x94NR1-(Alk)p-Q-(Alk)q-Axe2x80x94G
9. Exe2x80x94L+HO-(Alk)p-Q-(Alk)q-Axe2x80x94G
10. Exe2x80x94L+HS-(Alk)p-Q-(Alk)q-Axe2x80x94G
11. Exe2x80x94L+HNR1-(Alk)pxe2x80x94Q-(Alk)q-Axe2x80x94G
12. Exe2x80x94C(Y)xe2x80x94L+HNR1-(Alk)p-Q-(Alk)q-Axe2x80x94G
13. Exe2x80x94NR1xe2x80x94C(Y)xe2x80x94L+HNR1-(Alk)p-Q-(Alk)q-Axe2x80x94G
14. Exe2x80x94S(O)txe2x80x94L+HNR1-(Alk)p-Q-(Alk)q-Axe2x80x94G
15. Exe2x80x94NR1xe2x80x94S(O)txe2x80x94L+HNR1-(Alk)p-Q-(Alk)q-Axe2x80x94G
16. Exe2x80x94B-(Alk)p-OH+L-(Alk)q-Axe2x80x94G
17. Exe2x80x94B-(Alk)p-SH+L-(Alk)q-Axe2x80x94G
18. Exe2x80x94B-(Alk)p-NHR1+L-(Alk)q-Axe2x80x94G
19. Exe2x80x94B-(Alk)p-NHR1+Lxe2x80x94C(X)-(Alk)q-Axe2x80x94G
20. Exe2x80x94B-(Alk)p-NHR1+Lxe2x80x94C(X)xe2x80x94NR1-(Alk)q-Axe2x80x94G
21. Exe2x80x94B-(Alk)p-NHR1+Lxe2x80x94S(O)txe2x80x94(Alk)q-Axe2x80x94G
22. Exe2x80x94B-(Alk)p-NHR1+Lxe2x80x94S(O)txe2x80x94NR1-(Alk)q-Axe2x80x94G
23. Exe2x80x94B-(Alk)p-L+HO-(Alk)q-Axe2x80x94G
24. Exe2x80x94B-(Alk)p-L+HS-(Alk)q-Axe2x80x94G
25. Exe2x80x94B-(Alk)p-L+HNR1-(Alk)q-Axe2x80x94G
26. Exe2x80x94B-(Alk)pxe2x80x94C(X)-L+HNR1-(Alk)q-Axe2x80x94G
27. Exe2x80x94B-(Alk)p-NR1xe2x80x94C(X)xe2x80x94L+HNR1-(Alk)q-Axe2x80x94G
28. Exe2x80x94B-(Alk)p-S(O)txe2x80x94L+HNR1-(Alk)q-Axe2x80x94G
29. Exe2x80x94B-(Alk)p-NR1xe2x80x94S(O)txe2x80x94L+HNR1-(Alk)q-Axe2x80x94G
30. Exe2x80x94B-(Alk)p-Q-(Alk)q-L+G
31. Exe2x80x94B-(Alk)p-Q-(Alk)q-OH+Lxe2x80x94G
32. Exe2x80x94B-(Alk)p-Q-(Alk)q-SH+Lxe2x80x94G
33. Exe2x80x94B-(Alk)p-Q-(Alk)q-NHR1+Lxe2x80x94G
34. Exe2x80x94B-(Alk)p-Q-(Alk)q-NHR1+Lxe2x80x94C(X)xe2x80x94G
35. Exe2x80x94B-(Alk)p-Q-(Alk)q-NHR1+Lxe2x80x94C(X)xe2x80x94NR1xe2x80x94G
36. Exe2x80x94B-(Alk)p-Q-(Alk)q-NHR1+Lxe2x80x94S(O)txe2x80x94G
37. Exe2x80x94B-(Alk)p-Q-(Alk)q-NHR1+Lxe2x80x94S(O)txe2x80x94NR1xe2x80x94G
38. Exe2x80x94B-(Alk)p-Q-(Alk)q-L+HOxe2x80x94G
39. Exe2x80x94B-(Alk)p-Q-(Alk)q-L+HSxe2x80x94G
40. Exe2x80x94B-(Alk)p-Q-(Alk)q-L+HNR1xe2x80x94G
41. Exe2x80x94B-(Alk)p-Q-(Alk)q-C(X)xe2x80x94L+HNR1xe2x80x94G
42. Exe2x80x94B-(Alk)p-Q-(Alk)q-NR1xe2x80x94C(X)xe2x80x94L+HNR1xe2x80x94G
43. Exe2x80x94B-(Alk)p-Q-(Alk)q-S(O)txe2x80x94L+HNR1xe2x80x94G
44. Exe2x80x94B-(Alk)p-Q-(Alk)q-NR1xe2x80x94S(O)txe2x80x94L+HNR1xe2x80x94G
wherein L is a leaving group, such as chloro, bromo, iodo, triflyate, N-hydroxysuccinimide, N-hydroxybenzotriazole, tosylate, mesylate, methoxy, methylthiol, phenoxy, thiophenoxy and the like. Thioethers may be oxidized to the corresponding sulfinyl groups by oxidation with an oxidizing agent, such as hydrogen peroxide, sodium periodate and the like. Thioethers and sulfinyl groups may be oxidized to the corresponding sulfonyl groups by oxidation with an oxidizing agent, such as potassium peroxymonosulfate, potassium permanganate, hydrogen peroxide and the like.
The preparation of amidine groups, such as when B represents a xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94 or xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94 radical, is well known to those skilled in the art (see Baati et al., Synthesis 1999:927-929; Dunn, Compr. Org. funct. Group Transform. 5:741-82 and 1161-308, 1995; and Gautier et al., Chem. Amidines Imidates, Patai (Ed.), Wiley (1975), pp. 283-348). Guanidine groups, such as when B represents xe2x80x94N(R1)xe2x80x94C(Y)xe2x80x94N(R1)xe2x80x94 radical, can be prepared from urea groups (e.g., by reaction with POCl3 and a substituted amine in an organic solvent, such as toluene), from thiourea groups (e.g., by reaction with a substituted amine in the presence of CuSO4, SiO2 and a base, such as triethylamine, in an organic solvent such as tetrahydrofuran (Tet. Lett. 36:2841-4, 1995) or sodium periodate in the presence of base in dimethylformaide and water (Synlett 1997:1053-4)), from substituted cyanamide groups, xe2x80x94N(R)xe2x80x94CN (e.g., by reaction with a substituted amine), from imino ester amine groups, Rxe2x80x2Oxe2x80x94C(NR)xe2x80x94N(R)xe2x80x94 (e.g., by reaction with a substituted amine), or from imino thioester amine groups, Rxe2x80x2Sxe2x80x94C(NR)xe2x80x94N(R)xe2x80x94 (by reaction with a substituted amine (Synth. Commun. 29:1757-66, 1999).
Schemes 1 and 2 illustrate the preparation of compounds of the invention wherein G is a benzazepine type ring system. Compounds (21) and (22), wherein A1xe2x80x94 represents the radical Exe2x80x94B-(Alk)p-Q-(Alk)q-Axe2x80x94 or an intermediate radical (such as, Mxe2x80x94B-(Alk)p-Q-(Alk)q-Axe2x80x94, M-(Alk)p-Q-(Alk)q-Axe2x80x94, Mxe2x80x94Q-(Alk)q-Axe2x80x94, M-(Alk)q-Axe2x80x94, Mxe2x80x94Axe2x80x94 and the like wherein M is a reactive moiety such as an electrophile, nucleophile, leaving group or the like or a group that can be converted into an electrophile, nucleophile, leaving group or the like) that can be readily converted into the radical Exe2x80x94B-(Alk)p-Q-(Alk)q-Axe2x80x94, can be prepared from the corresponding amines (23) and (25), respectively, by alkylation, acylation, sulfonylation and the like, with A1xe2x80x94L, wherein L is a leaving group such as halide, tosylate, mesylate, carboxylic acid activating group (such as N-hydroxysuccinimide, carbodiimide (Tetrahedron 55:6813-6830, 1999), BOP (J. Org. Chem. 63:9678-9683, 1998) and the like) and the like. Alternatively, compounds (21) and (22) can be prepared by (a) nucleophilic displacement by A1xe2x80x94NH2 of leaving groups (L) on compounds (24) and (26), respectively, (b) reductive amination of compounds (24) and (26), respectively, wherein Lxe2x80x94X2xe2x80x94 and Lxe2x80x94X3xe2x80x94 represents a ketone or aldehyde, using A1xe2x80x94NH2 and a reducing agent (such as sodium cyanoborohydride, PtO2/H2 and the like), or (c) a mixture of both (a) and (b). Reaction of A1xe2x80x94NH2 with Lxe2x80x94X2xe2x80x94 and Lxe2x80x94X3xe2x80x94 can be simultaneous (one pot) or sequencial stepwise reactions. 
Schemes 3 and 4 illustrate the preparation of synthetic intermediates useful in the preparation of compounds (23) and (24). Scheme 3 addresses the preparation of the X2 portion of the compounds and Scheme 4 addresses the X3 portion of the compounds. Compound (28a/b) can be prepared from (27a/b), respectively, by oxidizing the hydroxy group to an aldehyde, such as by Swern oxidation or the like, and reacting the aldehyde with a nucleophile of R4 or R10, respectively, such as with organometallic agents (such 
as (R4)2CuLi, R10xe2x80x94Li or the like), or alternatively, oxidizing the hydroxy group to a carboxylic acid, reacting the acid with a nucleophile of R4 or R10, respectively, such as R4xe2x80x94Li, R10xe2x80x94MgBr or the like, and then reducing the resulting ketone to the hydroxy group, such as with sodium cyanoborohydride. Alcohol (28a/b) can be converted into sulfonyl compound (29a/b) by converting the hydroxy group into a leaving group (such as a halide, tosylate, mesylate, triflate or the like), nucleophilic displacement of the leaving group with a thiol salt (such as sodium sulfide or the like) and then coversion of the resulting thiol to a sulfonyl halide (such as Cl2/H2O oxidation or the like). Alcohols (27a/b) and (28a/b) can be converted into cyano compounds (30a/b) and (31a/b), respectively, by converting the hydroxy group into a leaving group as before followed by nucleophilic displacement of the leaving group with a cyanide salt (such as sodium cyanide or the like). Cyano compound (31a/b) can be prepared from cyano compound (30a/b) by nucleophilic displacement reaction with R4xe2x80x94L and R10xe2x80x94L, respectively, in the presence of base. Cyano compound (31a/b) can be reduced to the amine (32a/b), such as with BH3xe2x80x94Me2S or the like. Cyano compounds (30a/b) and (31a/b) can be hydrolyzed to a carboxylic acid which can then be esterified (P2) to form esters (33a/b) and (34a/b) respectively, or the acid of (34a/b) can be converted into an active ester (35a/b). As in the case of the cyano compound (30a/b), the ester compound (33a/b) can undergo a nucleophilic displacement reaction with R4xe2x80x94L and R10xe2x80x94L, respectively, in the presence of base (such as sodium hydride or the like) to prepare ester (34a/b). Esters (33a/b) and (34a/b) can undergo a condensation reaction with R6,7xe2x80x94C(O)xe2x80x94L, wherein R6,7xe2x80x94 represents radicals R6xe2x80x94 or R7xe2x80x94 as defined herein, in the presence of base, such as sodium hydride or the like, followed by hydroylsis and decarboxylation to yield ketones (36a/b) and (37a/b), respectively. Ketone (36a/b) can also undergo nucleophilc displacement of R4xe2x80x94L and R10xe2x80x94L, respectively, in the presence of base to yield ketone (37a/b). Ketone (37a/b) can undergo reductive amination with A1xe2x80x94NH2 or PNxe2x80x94NH2 (wherein PNxe2x80x94 is a nitrogen protecting group, such as benzyl, BOC or the like) or alternatively, can be reduced and the corresponding alcohol can be converted into a leaving group to yield compound (38a/b). The selection of which combination of moieties for X2 and X3 to be used in the preparation of compound (21) is well within the skill of one skilled in the art. 
Schemes 5, 6 and 7 illustrate the preparation of compounds (25) and (26). Schemes 5 and 6 address the preparation of the X2 portion of the compounds and Scheme 7 addresses the X3 portion of the compounds. Compound (40) can be prepared from aldehyde (39) as described above for compound (28). In Scheme 5, condensation of P2O2CCH2R12 (or alternatively, the corresponding Wittig reagent (Chem. Rev. 89:863-927, 1989) or Horner-Wadsworth-Emmons condensation (Tet. Lett. 24:4405-4408, 1983)) with compound (39) in the 
presence of base, such as sodium hydride or the like can yield the undaturated ester (41) which can undergo a Michael-type nucleophilic reaction to introduce the R4xe2x80x94 radical, such as with (R4)2Cu or the like, to yield ester (42). Alternatively, condensation of P2O2CCH2R12 with compound (40) in the presence of base, such as sodium hydride or the like, can yield ester (42) directly. Ester (42) can be converted into an activated ester (43) which can be reacted with A1xe2x80x94NH2 or PNxe2x80x94NH2. Alternatively, ester (42) can undergo a condensation reaction with R6,7xe2x80x94C(O)xe2x80x94L followed by hydroylsis and decarboxylation to yield ketone (44). Ketone (44) can undergo reductive amination with A1xe2x80x94NH2 or PNxe2x80x94NH2 or alternatively, can be reduced and the corresponding alcohol can be converted into a leaving group to yield compound (45). 
In Scheme 6, esters (33a) and (34a) can undergo a condensation reaction with R12xe2x80x94C(O)xe2x80x94L in the presence of base, such as sodium hydride or the like, followed by hydroylsis and decarboxylation to yield ketones (46) and (47), respectively. Ketone (46) can also undergo nucleophilc displacement of R4xe2x80x94L in the presence of base to yield ketone (47). Reduction of ketone (47) and conversion of the resulting alcohol to a leaving group (such as a halide, tosylate, mesylate, triflate or the like) as described above can yield compound (48). Nucleophilic displacement of the leaving group of compound (48) with a thiol salt (such as sodium sulfide or the like) and then coversion of the resulting thiol to a sulfonyl halide (such as Cl2/H2O oxidation or the like) can yield compound (49). 
In Scheme 7, ketone (50) can be prepared from the corresponding carboxylic acid by reacting the acid with a nucleophile of R6,7, such as R6,7xe2x80x94Li, R6,7xe2x80x94MgBr or the like, or alternatively, by acylation of the aromatic ring with R6,7xe2x80x94C(O)xe2x80x94L in the presence of a Friedel-Crafts catalyst, such as AlCl3 or the like, or alternatively, nucleophilic reaction of R6,7xe2x80x94C(O)xe2x80x94L or R6,7xe2x80x94CO2H with the corresponding organometallic salt of the aromatic ring. Ketone (50) can undergo reductive amination with A1xe2x80x94NH2 or PNxe2x80x94NH2or alternatively, can be reduced and the corresponding alcohol can be converted into a leaving group to yield compound (51). Sulfonyl compound (53) can be prepared from the corresponding thiol (52) (such as by Cl2/H2O oxidation or the like) which can be prepared by nucleophilic displacement of the corresponding halide with a thiol salt (such as sodium sulfide or the like). 
Alternatively, compounds (21) and (22) can be prepared by Heck Cyclization (Trans. Met. Org. Synth. 1:208-240, 1998) as shown in Schemes 8 and 9, respectively. Unsaturated esters (54) and (55), wherein L1 is a leaving group, such as halide, triflate or the like, can be cyclized in the presence of Pd(PPh3)4 to yield compounds (56) and (57), respectively. The double bond of compounds (56) and (57) can be reduced (such as by hydrogenation in the presence of Pd/C catalyst, magnesium in methanol or the like) and the ester groups can be readily converted into groups represented by R4xe2x80x94 radical using methods described above and standard methods well known to those skilled in the art. Unsaturated esters (54) and (55) can be prepared by nucleophilic displacement of the leaving group L of compounds (58) and (60), respectively, with amino compounds (59) and (61), respectively, which are commerically available or can be readily prepared from commerically available starting materials. In leu of the nitrogen protecting group PNxe2x80x94, A1xe2x80x94 or hydrogen atom may be used. 
Alternatively, compounds (54) and (55) can be cyclized by radical chain reaction utilizing an appropriate initiator, such as AIBN (Tet. Lett. 32:2829-2832, 1991), to esters (56) and (57), respectively, wherein the double bond is saturated.
Schemes 10 and 11 illustrate the preparation of compounds of the invention wherein G is a imidazolo-fused or triazolo-fused benzazepine type ring system. In Schemes 10 and 11, imidazolo-fused or triazolo-fused benzazepine type ring system (80) and (83) can be prepared from substituted imidazoles and triazoles (which are commercially available or readily prepared from commercially available starting materials) by alkylation of the imidazole or triazole nitrogen with alkylating agents (79) and (81). Cyclization can be effected by coversion of the hydroxy group of the alkylating agent into a leaving group which undergoes nucleophilic displacement upon metalation of the bromo (alternatively, chloro or iodo) group of the imidazole or triazole. One skilled in the art will recognize that other known processes, conditions and methods can be employed to effect the cyclization. Alkylating agents (79) and (81) can be prepared according to the processes described above. 
The reactions described above may be carried out in any number of solvents in which the reactants may be mutually soluble, including, for example, tetrahydrofuran, benzene, toluene, chloroform, dichloromethane, N,N-dimethylformamide, ethyl ether, dioxane, water, acetonitrile, or the like. Generally the reaction is carried out at a temperature of between xe2x88x9280xc2x0 C. and 150xc2x0 C., preferably, however, at room temperature. In certain cases, as noted in the examples provided herein, however, the temperature of the reaction may reach as high as or exceed about 360 xc2x0C.
The product and intermediates may be isolated or purified using one or more standard purification techniques, including, for example, one or more of simple solvent evaporation, recrystallization, distillation, sublimation, filtration, chromatography, including thin-layer chromatography, HPLC (e.g., reverse phase HPLC using, for example, dilute trifluoroacetic acid in water, acetonitrile, or methanol mixtures as eluent), column chromatography, flash chromatography, radial chromatography, trituration, and the like.
In the preparation of the compounds of the invention, one skilled in the art will understand that one may need to protect or block various reactive functionalities on the starting compounds or intermediates while a desired reaction is carried out on other portions of the molecule. After the desired reactions are complete, or at any desired time, normally such protecting groups will be removed by, for example, hydrolytic or hydrogenolytic means. Such protection and deprotection steps are conventional in organic chemistry. One skilled in the art is referred to xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d McOmie, Ed., Plenum Press, New York, N.Y.; and xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Greene, Ed., John Wiley and Sons, New York, N.Y. (1981) for the teaching of protective groups which may be useful in the preparation of compounds of the present invention.
Alternate means beyond those described above for preparing the compounds of the invention will be apparent to one skilled in the art and the noted general procedures are not to be construed as limiting the invention. To more fully understand the invention, including methods of preparing compounds of the invention, the following non-limiting examples are provided. The reader will appreciate that starting materials not otherwise described herein are either available commercially or can be prepared from commercially available compounds by methods generally known in the art.
Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents such as dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (CH2Cl2), and toluene, dioxane were obtained from Aldrich Chemical Company in Sure/Seal bottles. All reactions involving air- or moisture-sensitive compounds were performed under a N2 atmosphere. Flash chromatography was performed using ICN Biomedicals (SiliTech 32-63D 60A). Thin-layer chromatography (TLC) was performed with Analtech or Whatman silica gel TLC plates (250 xcexcm). Preparatory TLC was performed with Whatman silica gel TLC plates (2000 xcexcm). 1H NMR spectra were determined with superconducting FT NMR spectrometers operating at 400 and 500 MHz. Chemical shifts are expressed in ppm downfield from internal tetramethylsilane. Significant 1H NMR data are reported in the following order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; quin, quintet), number of protons, and coupling constants in Hz. Elemental analyses were performed by Atlantic Microlab, Inc., Norcross, Ga. Melting points were determined with a Buchi 535 capillary melting point apparatus and are uncorrected. Low resolution mass spectra (MS) were determined on a Perkin Elmer-SCIEX API 165 mass spectrometer using APCI or ES ionization modes (positive or negative). High resolution mass spectra (HRMS) were performed by Mass Consortium, San Diego, Calif. using FAB ionization.